Review of Developments in GMP and the Regulation of Medicines March 2022
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INTRODUCTION
During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from the UK, EU, USA, PIC/S and Australian regulatory authorities.
The topics covered in this edition of the “Update” include:
MHRA
New year, new standards for investigational medicines
Public Consultation on new Clinical Trials Legislation (Blog)
UK Regulator’s experience of clinical trials during the Covid-19 pandemic (Blog parts 1&2)
Initiation of DARWIN EU® Coordination Centre
European medicines regulatory network adopts EU common standard for electronic product information
Reflection paper on the interpretation of Article 18(7) of Regulation (EU) 2019/6
EMA as a Stringent Regulatory Authority (SRA) in the WHO-led Collaborative Registration Procedure
Big Data Highlights
EDQM remote inspections: from pilot phase to a permanent element of EDQM’s inspection scheme
Webinar: What has changed in the Ph. Eur. General Notices?
EDQM reminds CEP holders of their responsibilities towards their customers
Reference standards
Formal meetings between FDA and sponsors or requestors of over-the-counter (OTC) monograph drugs.
Immunogenicity information in human prescription therapeutic protein and select drug product labeling —content and format.
Drug Product Tracing: The Effect of Section 585 of the FD&C Act instead of FDA’s guidance on uniform national policy
PIC/S
New PIC/S Executive Bureau
Revision of PIC/S GMP Guide (PE 009-16)
Hydroxyethyl-starch solutions for infusion recommended for suspension from the market
EMA recommends approval of Spikevax for children aged 6 to 11
EMA recommends authorisation of booster doses of Comirnaty from 12 years of age
Electronic product information: new report shows it is time to move from principles to action
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
New year, new standards for investigational medicines
Monday 31 January 2022 saw the Clinical Trial regulation (CTR) come into force in the European Union and with it, the revised Annex 13 of EU GMP.
Having left the European Union, the new EU CTR will not be applicable in the UK. UK requirements will remain unchanged pending completion of the consultation on the new proposals for the future of UK clinical trial legislation. The changes in GMP guidance will however still impact manufacturers and importers of investigational medicinal products (IMPs) in the UK. UK will remain aligned with the internationally harmonised standards of PIC/S and the EU, including requirements for the Qualified Person.
Implementation in the UK
The revised Annex 13 is now effective (from 31 January 2022), however pending completion of the UK’s future clinical trial legislation, UK will also continue to apply the January 2010 version of Annex 13 with respect to:
labelling requirements
two-step release procedure
handling and shipping of IMPs
contractual arrangements between the trial Sponsor and IMP manufacturer
Public consultation on new clinical trials legislation (Blog)
Following the UK’s exit from the European Union, the Medicines and Medical Devices Act allows UK the opportunity to update its current legislation in relation to clinical trials (Statutory Instrument 2004/1031, and its numerous amendments). The new proposals are based on feedback from stakeholders and an Expert Working Group, which included representatives from academia, industry, and patient groups. MHRA would like to update current legislation to allow it to streamline the regulation of clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.
MHRA is seeking the views of clinical trial participants, researchers, developers, manufacturers, sponsors, investigators, healthcare professionals and the wider public to help shape improvements to the legislation for clinical trials.
The consultation will close at 11pm on Monday, 14 March 2022.
UK Regulator’s experience of clinical trials during the Covid-19 pandemic (Blog parts 1&2)
In part 1 of this series, MHRA explored as an introduction how it initially responded to the Covid-19 pandemic to move faster in the set-up and approval of clinical trials. Subsequently in part 2 it looked at the unprecedented challenges it faced in each area and the lessons it has learned during the last two years.
Europe
EMA
Initiation of DARWIN EU® Coordination Centre
The role of the Coordination Centre is to develop and manage a network of real-world healthcare data (RWD) sources across the EU and to conduct scientific studies requested by medicines regulators and, at a later stage, requested by other stakeholders. The vision of DARWIN EU® is to give EMA and national competent authorities in EU Member States access to valid and trustworthy real-world evidence (RWE), for example on diseases, patient populations, and the use, safety and effectiveness of medicines, including vaccines, throughout the lifecycle of a medicinal product. By supporting decision-making on the development, authorisation and surveillance of medicines, a wide range of stakeholders will benefit, from patients and healthcare professionals to healthcare assessment bodies and the pharmaceutical industry. Additionally, DARWIN EU® will provide an invaluable resource to prepare for and respond to future healthcare crises and pandemics.
EMA will be working with Erasmus University Medical Center Rotterdam to establish the DARWIN EU® Coordination Centre.
A multi stakeholder information webinar was organised by EMA for 24 February 2022 to introduce the establishment of DARWIN EU, highlight opportunities for collaboration and answer questions.
European medicines regulatory network adopts EU common standard for electronic product information
This will pave the way for wider dissemination of the unbiased, up-to-date information on all medicines available to patients in the EU through an ever-expanding range of electronic channels. The product information (PI) of a medicine includes the package leaflet for patients and the summary of product characteristics (SmPC) for healthcare professionals. These documents accompany every single medicine authorised in the EU and explain how it should be used and prescribed. The ePI can be updated immediately, as soon as new information becomes available. The structured nature of ePI will also offer new opportunities to personalise the PI to individual needs and to make it more easily accessible to users with diverse abilities. Future developments of the ePI could include functionalities such as automatic update notifications, access to supportive videos or audio content and online adverse-reaction reporting tools.
Reflection paper on the interpretation of Article 18(7) of Regulation (EU) 2019/6
Regulation (EU) 2019/61 (VMP-Reg), which lays down the rules for the marketing of veterinary medicinal products (VMPs) in the European Union (EU) and the European Economic Area (EEA), will be applicable from 28 January 2022 and replace Directive 2001/82/E.
Article 18 of the VMP-Reg generally lays down provisions related to the granting of a marketing authorisation for generic VMPs, with Article 18(7) specifically concerning provisions for the performance of an environmental risk assessment (ERA) for generic VMPs.
The present reflection paper aims at providing an approach to applying Article 18(7)
EMA as a Stringent Regulatory Authority (SRA) in the WHO-led Collaborative Registration Procedure
Since 2015 EMA participates as a Stringent Regulatory Authority (SRA) in the WHO-led Collaborative Registration Procedure using Stringent Regulatory Authorities (SRA CRP), which facilitates the registration of medicines in non-EU countries where regulatory resources may be limited.
This allows marketing authorisation holders of centrally authorised medicines or holders of EU-M4all opinions to share full assessment reports and inspection reports with the authorities in non-EU countries where they seek authorisation. The aim is to accelerate authorisation based on the SRA assessment while allowing competent authorities which might have limited regulatory resources to fulfil their regulatory responsibilities and make their own decisions.
An analysis of public health impact and participant experience during a pilot found the SRA CRP enables faster access to quality-assured, safe and effective medicines for patients in need. It reduces the time from submission to authorisation, avoids duplication and decreases workload in resource-limited countries, leading to greater efficiency in regulatory processes.
Big Data Highlights
Issue 1 of the new quarterly update on implementation activities of the HMA-EMA Big Data Steering Group has been published.
EDQM
EDQM remote inspections: from pilot phase to a permanent element of EDQM’s inspection scheme
The pilot phase, which started in November 2020 and was based on the voluntary participation of inspectorates and companies, was completed at the end of 2021. The objective of conducting distant assessments via an official review of activities, documents, facilities, records, etc. in real-time with live interaction with the company and a reliable video feed from the facilities was achieved.
After evaluating the results and achievements obtained during the pilot phase of the remote inspection project, the EDQM has concluded that the Real-Time Remote Inspections (RTEMIS) approach is suitable to become an integral part of its system for the supervision of manufacturers of active substances. It will therefore complement existing tools, such as on-site inspections and documentation-based GMP assessment.
All companies notified for an RTEMIS inspection are therefore expected to ensure that appropriate IT infrastructure and hardware are in place by the time of the inspection. Further technical details will be shared with companies concerned at the time of the notification and during the preparatory phase of the inspection.
Webinar: What has changed in the Ph. Eur. General Notices?
The General Notices is the European Pharmacopoeia (Ph. Eur.) go-to chapter that contains important information applicable to all Ph. Eur. texts. Its content is relevant for any user seeking to understand not just the conventional expressions and terminology used throughout the Ph. Eur. but also how the texts interconnect and how they should be applied. This major chapter has now been fundamentally revised and the new version published in Supplement 10.7 of the Ph. Eur.
EDQM reminds CEP holders of their responsibilities towards their customers
CEP holders have obligations towards the marketing authorisation holders in order to enable them to fulfil their respective legal responsibilities. Recent issues have demonstrated the lack of knowledge of some CEP holders regarding those obligations. In order to clarify the issue, EDQM has summarised CEP holders’ responsibilities in a guidance document, which is now available on the EDQM website.
Reference standards
2 new reference standards and 19 replacement batches have been released.
United States of America
The US Food and Drug Administration (USFDA)
Formal meetings between FDA and sponsors or requestors of over-the-counter (OTC) monograph drugs guidance for industry
This draft guidance specifies the procedures and principles for formal meetings between FDA and sponsors or requestors for an OTC monograph drug. In doing so, it describes procedures under which meeting requesters can meet with appropriate FDA officials to obtain advice on the studies and other information necessary to support submissions under section 505G of the FD&C Act, to obtain advice on other matters relevant to the regulation of nonprescription drugs, and to obtain advice on the development of new OTC monograph drugs.
This guidance also specifies procedures to facilitate efficient participation in joint meetings by multiple meeting requesters and/or organizations nominated by them to represent their interests. This includes meetings conducted in any format (i.e., face to face, teleconference / videoconference, or written response only (WRO)).
This guidance discusses the principles of good meeting management practices and describes standardized procedures for requesting, preparing, scheduling, conducting, and documenting such formal meetings.
Immunogenicity information in human prescription therapeutic protein and select drug product labeling —content and format.
The purpose of this draft guidance is to assist applicants with incorporating immunogenicity information into the labeling of human prescription biological products, specifically therapeutic protein products, and of select drug products that have immunogenicity assessments.
This guidance provides recommendations to help ensure that clinically relevant immunogenicity information is included in and distributed appropriately across sections and subsections of product labeling, in accordance with regulatory requirements for the content and format of human prescription drug and biological product labeling. The goal of appropriate inclusion and distribution of clinically relevant immunogenicity information in the labeling is to enable health care practitioners to easily access, understand, and use this information to inform prescribing decisions and patient management, and to help enable safe and effective use of applicable products.
This guidance does not apply to products intended to induce a specific immune response to prevent or treat a disease or condition (such as vaccines and allergenic products).
Drug Product Tracing: The effect of section 585 of the FD&C Act instead of FDA’s guidance on uniform national policy
FDA is issuing these questions and answers to assist industry and State and local governments in understanding the effects of section 585 (Uniform National Policy) of the FD&C Act (21 U.S.C. 360eee- 4), added by Title II of the Drug Quality and Security Act (DQSA), which was enacted on November 27, 2013, on drug product tracing. Title II, (also referred to as the Drug Supply Chain Security Act (DSCSA)), establishes a Federal system for tracing prescription drug products through the pharmaceutical distribution supply chain and requires trading partners to pass, receive, and maintain certain product and distribution information. Section 585 requires there be a uniform national policy, pre-empting States from establishing or continuing in effect certain standards and requirements. FDA is issuing this guidance to:
(1) help industry and States understand the law as it is currently in effect; and
(2) clarify the effect of section 585(a) on any regulation of drug product tracing by States.
International
PIC/S
New PIC/S Executive Bureau
A new PIC/S Executive Bureau (EB) took office on 1 January 2022. The PIC/S Committee unanimously elected Mr Paul Gustafson (Canada / ROEB) as Chairperson for the period 2022-2023. Mr Gustafson will be assisted by Ms Susan Laska (US FDA), PIC/S Deputy Chairperson.
Revision of PIC/S GMP Guide (PE 009-16)
Geneva, 1 February 2022: The PIC/S GMP Guide to Good Manufacturing Practice (GMP) for Medicinal Products has been revised to include:
a revised Annex 13 on the Manufacture of Investigational Medicinal Products; and
a new Annex 16 on the Certification by the Authorised Person and Batch Release
PIC/S Annex 13 has been revised based on EC Regulation No. 536/2014 on Clinical Trials, which will replace EU Annex 13. This is in line with the Co-operation Agreement between PIC/S and EMA, which provides that the PIC/S and EU GMP Guides should be harmonised with the aim of keeping GMP standards equivalent, thus facilitating the exchange and use of information concerning the manufacture of medicinal products.
PIC/S Annex 16 is a new annex to the PIC/S GMP Guide. Historically, PIC/S did not adapt EU Annex 16, when it was adopted as part of the EU GMP Guide. Initially, PIC/S considered this annex to be EU-specific and difficult to transpose for PIC/S purposes.
Following a consultation of PIC/S Participating Authorities in 2017, it was agreed to make an attempt to transpose EU Annex 16, considering that a PIC/S adaptation could offer added benefit to better convey expectations associated with product release and further international harmonisation efforts in line with PIC/S’ mission to lead the international development, implementation and maintenance of harmonised GMP standards and quality systems of inspectorates in the field of medicinal products. PIC/S also agreed that elements in Annex 16 related to imported medicinal products would be voluntary, dependent on national law.
The revised GMP Guide (PE 009-16), with the revised Annex 13 and the new Annex 16, entered into force on 1 February 2022.
Products
Hydroxyethyl-starch solutions for infusion recommended for suspension from the market
The safety of HES solutions for infusion was reviewed in three separate procedures 2 in 2013 and the latest in 2018. A number of restrictions and measures to minimise the risk of kidney injury and death in certain patients (those critically ill, with burn injuries or with sepsis, a bacterial infection in the blood) were put in place at the time.
As a result of the 2018 review the use of HES solutions for infusion was further restricted to accredited hospitals, and healthcare professionals prescribing or administering the medicines had to be trained in their appropriate use.
The Pharmacovigilance Risk Assessment Committee (PRAC) reviewed the results from this study, which show that HES solutions for infusion are still being used outside the recommendations included in the Product information The Committee concluded that the further restrictions introduced in 2018 have not sufficiently ensured that the medicines are used safely, and that HES solutions continue to be used in certain groups of patients in whom serious harm has been demonstrated. In view of the serious risks that certain patient populations are still exposed to, the PRAC therefore recommended the suspension of the marketing authorisations for HES solutions for infusion in the EU. The PRAC recommendation was approved by a majority vote by the Coordination Group for Mutual Recognition and Decentralized Procedures – Human (CMDh), which adopted its position on 23 February 2022.
As the position was adopted by majority vote, it will now be sent to the European Commission, which will take an EU-wide legally binding decision in due course
[An example of the regulators Risk Based decision making where risk of harm to patient v potential to save a life possibly appear to be in conflict. Obviously not an easy decision, MBH]
EMA recommends approval of Spikevax for children aged 6 to 11
EMA’s human medicines committee CHMP has recommended granting an extension of indication for the COVID-19 vaccine Spikevax to include use in children aged 6 to 11. The vaccine, developed by Moderna, is already approved for use in adults and children aged 12 and above.
The dose of Spikevax in children from 6 to 11 years of age will be lower than that used in people aged 12 and above (50 µg compared with 100 µg). As in the older age group, the vaccine is given as two injections in the muscles of the upper arm, four weeks apart.
EMA recommends authorisation of booster doses of Comirnaty from 12 years of age
EMA’s CHMP has recommended that a booster dose of the COVID-19 vaccine Comirnaty may be given where appropriate to adolescents from 12 years of age. Comirnaty is already authorised in the EU as a 2-dose primary course in adolescents1 (as well as adults and children from 5 years of age) and a booster dose is currently authorised from 18 years of age.
Documents
Electronic product information: new report shows it is time to move from principles to action
A new report run by the European Association of Hospital Pharmacists (EAHP) explores the potential future of digitalisation and notably the use of electronic product information (ePI) in hospitals.
The report is based on the results of a survey that was carried out in cooperation with the Inter-Association Task Force for electronic product information (IATF) composed of Medicines for Europe, EFPIA (European Federation of Pharmaceutical Industries and Associations), and AESGP (Association of the European Self-Care Industry) from March to April 2021 and targeted hospital pharmacists in 36 European countries, ultimately receiving 534 answers. Findings show that the adoption of ePI could make access to product information easier for both healthcare professionals and patients.
The survey reveals that patients are usually not provided with paper package leaflets, and only 21% of respondents revealed that medicines information is provided orally to patients.
According to Medicines for Europe, EFPIA, and AESGP, the results of the survey clearly show the need to integrate future looking and practical proposals for an ePI in the upcoming revision of the EU pharmaceutical legislation. Such a proposal should contribute to patient access to information about their medicine, and when appropriate the reduction of paper waste.
[On a number of occasions I have seen, particularly in small markets supplied from large companies, where a single delivery of product can amount to more than a year or two’s supply for that small market. Subsequently, product has had to be recalled from the marke,t or additional facilities approved for re-packaging of product where e.g PI leaflet and registered detail are no longer consistent. ePI could well be one means of addressing this issue. MBH]
And finally…
Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.
We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.